title: Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.
abstract: Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.
authors.affiliation: 1] Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia [2] Department of Histopathology, Sullivan Nicolaides Pathology, Taringa, QLD, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Williamson
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Pearson
authors.forename: Rhiannon J
authors.initials: RJ
authors.lastname: Walters
authors.forename: Belinda
authors.initials: B
authors.lastname: Nagler
authors.forename: David
authors.initials: D
authors.lastname: Packenas
authors.forename: Aung K
authors.initials: AK
authors.lastname: Win
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Haydon
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Dallas R
authors.initials: DR
authors.lastname: English
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D000071616:CDX2 Transcription Factor; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D055271:Mucin 5AC / Q000032:analysis / Q000096:biosynthesis; D055262:Mucin-2 / Q000032:analysis / Q000096:biosynthesis; D055257:Mucin-5B / Q000032:analysis / Q000096:biosynthesis; D055272:Mucin-6 / Q000032:analysis / Q000096:biosynthesis; D009077:Mucins / Q000032:analysis / Q000096:biosynthesis*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; C524734:MUC6 protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D055257:Mucin-5B; D055272:Mucin-6; D009077:Mucins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf